VITAMINS AND HORMONES Hedgehog Signaling

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1 VOLUME EIGHT VITAMINS AND HORMONES Hedgehog Signaling Editor-in-Chief GERALD LITWACK, PhD Toluca Lake, North Hollywood, California AMSTERDAM BOSTON HEIDELBERG LONDON NEW YORK OXFORD PARIS SAN DIEGO SAN FRANCISCO SINGAPORE SYDNEY TOKYO Academic Press is an of Elsevier

2 CONTENTS Contributors Preface xv xxi 1. Hedgehog Signaling 1 Siu Wah Choy and Shuk Han Cheng Hedgehog Ligands 2 II. Hedgehog Signaling 4 III. Hedgehog Signaling in Zebrafish Eye Vesicle Patterning 5 IV. Hedgehog Signaling in Zebrafish Photoreceptor Differentiation 7 V. Hedgehog Signaling in Zebrafish Inner Nuclear Layer 10 VI. Hedgehog Signaling in Zebrafish Ganglion Cell Differentiation 11 References Canonical and Noncanonical Signaling in Hematological Malignancies 25 Fritz Aberger, Daniela Kern, Richard and Tanja Nicole Hedgehog Introduction 26 II. Regulation of Canonical HH Signaling and Its Implication in Cancer 26 Modulation of Activity 32 IV. Hedgehog in and Hematopoietic Stem Cells 35 From HSC to 38 VI. T- and Malignancies 39 VII. Outlook 44 Acknowledgments 46 References Noncanonical Hedgehog Signaling 55 Donna Brennan, Xiaole Chen, Lan Cheng, My Mahoney, and Natalia A. Riobo Definition 56 II. Type Noncanonical Signaling: Pathways Engaged Exclusively by 56 Type II Noncanonical Signaling: Pathways Engaged by 61 IV. Noncanonical Hh Signaling in Drosophila 67 V. Concluding Remarks 68 References 68 VII

3 4. Protein Nuclear Localization Signal 73 Minoru and Jun Aruga Introduction 74 II. Nuclear Localization Signal and Nuclear Export Signal 74 NLS and NES Mapping 75 IV. Sequence Comparison of Gli NLSs-NLSs in ZF Domains 79 Predicted 3D Structure of Gli NLS 81 NLS Control of Subcellular Localization in Hh Signaling 83 VII. Perspectives 86 References Mammalian of Drosophila Fused Kinase 9 1 Maloverjan and Marko Piirsoo Introduction 9 2 II. The Major Steps of Hh Signaling 93 Proteins are Transcription Factors Mediating Hh Activities 94 IV. Hedgehog Signaling Complex is Responsible for Regulation of ci Protein 96 V. Regulation of Gli Proteins 98 VI. Fu is a Protein Kinase Playing Catalytic and Regulatory Roles in ci regulation 99 Protein Kinases Participating in the Regulation of Gli Proteins 100 Controversial Roles of Stk IX. The Role of Ulk3 in Shh Signaling Pathway 103 X. An Emerging Shh Signaling Model Involving 106 Acknowledgments 107 References 6. Identification, Functional Characterization, and Pathobiological Significance of Isoforms in Human Cancers 115 Richard L. Carpenter and Hui-Wen Lo Introduction II. Structures and Properties of Isoforms 117 III. Regulation of Isoforms by Canonical and Noncanonical Pathways 121 IV. Isoforms and Malignant Phenotypes of Cancer 126 V. Conclusion and Future Directions Acknowledgments References

4 ix 7. Proteins: Their Mechanisms of Action, Physiological Functions, and Roles in Disease 141 Kristin Gary ZeRuth, Hong Soon Kang, and Anton M. Jetten Introduction 142 II. Mechanism of Action of Proteins 144 Role of Glis Proteins in Renal Physiology and Pathology 151 IV. Role of Glis3 in Pancreas Physiology and Pathology 155 V. Glis Functions in Other Tissues 160 VI. Conclusion 163 Acknowledgments 163 References Sonic Hedgehog Regulates Wnt Activity During Neural Circuit Formation 173 Nicole H. Wilson and Esther T. Stoeckli Introduction 174 II. Shh and Wnt Signaling: Canonical Signaling Pathways 174 III. Patterning and Morphogenesis of the Neural Tube 177 Establishment of Neuronal Polarization 184 V. Axon Guidance 186 VI. Synapse Formation 195 VII. Other Factors Influencing Shh and Wnt Pathways 197 VIM. Conclusions and Future Directions 200 References Control by Interplay 211 Alberto Gulino, Lucia Di Marcotullio, Gianluca Canettieri, Enrico De and Isabella Screpanti Introduction 212 II. Regulation of Hh Signaling 213 Increasing the Complexity of Hh Signaling in Vertebrates: The and Cul3-Dependent Processes 214 IV. An Alternative Control by the HECT-Type Itch E3 Ubiquitin Ligase-Based Processing 215 V. Activation of Itch Function by Numb 216 VI. Acetylation to Ubiquitination Connection in Hh Signaling 217

5 VII. Implications of Events for Cell Development and 218 VIII. Implications for Interplay in Cell Development and Cancer Control 220 IX. Conclusions 221 Acknowledgments 222 References of Hedgehog Proteins 229 John A. Buglino and Marilyn D. Resh Introduction to Protein Palmitoylation 230 II. Palmitoylation of Hedgehog Proteins 231 III. Palmitoylation of Other Secreted Proteins 240 IV. The MBOAT Family of Acyltransferases 242 Conclusions and Future Directions 246 Acknowledgments 246 References Phosphorylation Regulation of Hedgehog Signaling 253 Introduction 253 II. Phosphorylation of the Transcription Factor in Hh Signaling 255 Phosphorylation of Receptor in Hh Signaling 257 IV. Other Phosphorylation Events in Hh Signaling 260 Nonconserved Phosphorylation 262 Phosphatases in Hh Signaling 263 Differential Phosphorylation of Hh Signaling Components 264 Acknowledgments 266 References Protein Kinase A Activity and Hedgehog Signaling Pathway 273 Kotani Introduction II. Function of PKA in Hedgehog-Responsive Cells 275 Activation of PKA 279 PKA Activity in Hedgehog-Responding Cells 284 V. Perspectives 286 Acknowledgments 287 References 287

6 xi 13. Phosphorylation of Gli by camp-dependent Protein Kinase 293 Yoshinari Asaoka Introduction 294 II. camp-dependent Protein Kinase 295 III. Hedgehog Signaling and camp-dependent Protein Kinase 297 IV. Gli Transcription Factors and camp-dependent Protein Kinase 298 V. Conclusions 301 References ZFP932 Suppresses Cellular Hedgehog Response and Transcription 309 G. Jason Huang, Zhenhua He, and Liang Ma Introduction 310 II. Characterization 312 III. ZFP932 Expression 315 IV. ZFP932 Represses Cellular Hedgehog-Signaling Response 327 V. ZFP932 Regulates Osteoblast Differentiation 328 VI. Conclusion 330 Acknowledgments 330 References A New Era for an Ancient Drug: Arsenic Trioxide and Hedgehog Signaling 333 M. and Aykut Historic Use of Arsenic in Medicine 334 II. Molecular Mechanisms of Arsenic in Cancer Therapy 335 III. Role of Hedgehog Signaling in Cancer 339 IV. Effect of Arsenic on Hh Signaling 342 V. Conclusions 345 References Aberrations and Therapeutics Involving the Developmental Pathway Hedgehog in Pancreatic cancer 355 Fergal C. Kelleher and Raymond Introduction 356 II. The Hedgehog Pathway 357 III. Hedgehog Therapeutics 362 IV. Conclusion 375 References 375

7 XII Contents 17. Sonic Hedgehog Signaling and Potential Therapeutic Indications 379 Nicholas C. and Kaine Onwuzulike Sonic Hedgehog Discovered (Shh) 380 II. Shh Signaling in Vertebrates III. Shh Second Messenger Systems 383 Shh in Stem Cell Proliferation 385 V. Shh in Oncogenesis 387 VI. Shh in Injury of the CNS 389 VII. Conclusion 393 References Sonic Hedgehog on Microparticles and Neovascularization 395 Raffaella Soleti and Maria Carmen Martinez Introduction II. Neovascularization 397 III. Sonic Hedgehog 405 Microparticles 415 V. Conclusion 424 References up the Neurons: Revival or Enervation? 439 Sayantani Ghosh, Arunabha Chakrabarti, and Debashis Mukhopadhyay Introduction 440 II. The "Patched" Transmission 442 Expression in Neural Tissues 443 IV. Ptchi in Disease, Development, and Injury 445 V. Conclusion 453 Acknowledgments 454 References Activation of Hedgehog Pathway in Gastrointestinal Cancers 461 Ling Yang, Xiulan Su, and Jingwu Xie Introduction II. Activation of the Hh Pathway in Esophageal Cancer 462 Activation of the Hh Pathway in Gastric Cancer IV. Activation of the Hh Pathway in Colorectal Cancer 466 V. Summary References

8 xiii 21. The Role of Sonic Hedgehog as a Regulator of Gastric Function and Differentiation 473 Rui Feng, Chang Xiao, and Yana Zavros Introduction 474 II. Hh in the Adult Stomach 474 The Potential Role of Sonic Hh as a Gastric Hormone 481 IV. Conclusions and Future Directions 484 Acknowledgment 485 References Sonic Hedgehog-Mediated Synergistic Effects Guiding Angiogenesis and Osteogenesis 491 Sabine Fuchs, Eva and Charles James Kirkpatrick General Introduction 492 II. General Aspects of Shh Signaling 492 The Role of Hh Morphogens in Bone Development and Repair 493 IV. Shh: Potential Candidate Linking Angiogenesis and Osteogenesis 494 V. Effects of Shh on Angiogenesis, Vessel Maturation, and Osteogenesis 494 VI. Coculture Models as In Vitro Models to Investigate Effects of Shh on Osteogenesis and Angiogenesis 496 VII. Effects of Shh on Angiogenesis in a Coculture Model 497 VIM. Effects of Shh on Osteogenesis in a Coculture Model 499 IX. Future Therapeutical Options and Delivery Strategies 501 References Hedgehog Inhibition as an Anti-Cancer Strategy 507 G. Praveen Raju and Diane Introduction 508 II. Hh Signaling in Normal Development 508 Hh Pathway Alterations in Cancer 509 IV. Targeted Therapies for Hedgehog Dependent Cancers 512 V. Conclusions and Future Directions 516 Acknowledgments 518 References 519 Index 523